tbuckley/cabot-search huggingface dataset:
Establishment of a visualized mouse orthotopic model of nasopharyngeal carcinoma.
Authors: Min Kang, Wei Chen, Sixia Chen, Li Jiang, Gege Shu, Yuanxiu Yin, Zhipeng Quan, Ziyan Zhou, Mingjun Shen, Yating Qin, Chaolin Yang, Xuejin Su, Weimin Chen
Journal: Journal of Clinical Oncology (2022)

e18048 Background: Nasopharyngeal carcinoma, one of the most common head and neck tumors, is particularly prevalent in Southeast Asia and is characterized by high rates of metastasis and recurrence. Although mouse orthotopic tumor models are commonly employed in studies investigating the mechanisms underlying tumor development and progression, as well as preclinical treatment, currently no such model exists for nasopharyngeal carcinoma. The aim of the current study is to, therefore, establish an orthotopic murine model for nasopharyngeal carcinoma. Methods: To this end, human nasopharyngeal carcinoma C666-1-luc cells, stably expressing the firefly luciferase gene, were injected subcutaneously into the right axilla of BALB/C nude mice. Four weeks later, the resulting subcutaneous tumors were cut into small blocks and grafted into the nasopharynx of immunodeficient BALB/C nude mice to induce tumor formation. Tumor growth was monitored by bioluminescence imaging and small animal magnetic resonance imaging. The histological and immunological antigen expression associated with orthotopic nasopharyngeal carcinoma were analyzed by tissue section analysis and immunohistochemistry (IHC). Results: The tumor formation rate was over 90%. Fluorescence signal detection, micro-magnetic resonance imaging and hematoxylin and eosin staining revealed the successful growth of tumors in the nasopharynx of nude mice. Moreover, IHC analysis detected positive CK, CK5/6, P40 and P63 expression in the mouse orthotopic tumors, which is consistent with the reported antigen expression in the nasopharyngeal tumors of patients. Conclusions: Hence, we successfully established a mouse orthotopic model of nasopharyngeal carcinoma that is highly reproducible, and simple in operation, with low mortality and high tumor formation rates. Moreover, this model facilitates real-time monitoring of tumor growth via in vivo imaging technology, thus, providing a platform for researching nasopharyngeal carcinoma that is more conducive to preclinical research.
Outcome of patients with PSMA PET/CT screen failure by VISION criteria and treated with 177Lu-PSMA therapy: A multicenter retrospective analysis.
Authors: Masatoshi Hotta, Johannes Czernin, Andrei Gafita, Jeremie Calais
Journal: Journal of Clinical Oncology (2022)

5042 Background: The VISION trial showed that 177Lu-PSMA prolongs survival and improves the quality of life of patients with advanced mCRPC. It used PSMA-PET/CT to select patients for inclusion. The screen failure rate was “only” 12.6% (126/1003) and some have argued that the trial could have been positive even in an unselected population. It remains unknown whether the VISION-PET criteria were appropriate to stratify patients into likely responders versus non-responders to177Lu-PSMA. Here, we evaluated the outcome of patients who would have been excluded by the VISION-PET criteria and were nevertheless treated with 177Lu-PSMA. Methods: Patients treated with ≥1 cycle of 177Lu-PSMA between 11/2017 and 07/2021 (n = 74) who were registered in our institutional database and those enrolled in a multicenter dataset published previously (n = 230) (Gafita A, Lancet Oncol 2021) were retrospectively studied. One dual certified nuclear medicine and radiology reader reviewed baseline PSMA PET/CT studies and classified the patients as eligible (VISION-PET-E) or screen failure (VISION-PET-SF) based on the VISION-PET criteria: 1) absence of metastatic lesion(s) with uptake &gt; liver background (i.e., low PSMA expression) or 2) presence of ≥ 1 metastatic lesion measurable by CT (≥ 1 cm for bone lesions with soft-tissue component (M1b) and solid/visceral organs lesions (M1c); ≥ 2.5 cm for lymph nodes lesions (N1-M1a)) with uptake ≤ liver background (i.e., PSMA-negative lesions). Outcome measures were PSA response rates (decline of ≥50% (PSA50RR), any decline (anyPSARR)), PSA-progression free-survival (PSA-PFS), and overall survival (OS). Results: 3/304 patients (1%) were excluded (lost to follow-up (n = 2), missing CT data (n = 1)). The median follow-up time was 22.5 (range: 2.1-62.3) months. 272/301 (90.4%) were VISION-PET-E, while 29/301 (9.6%) were VISION-PET-SF: 8/301 (2.7%) and 21/301 (7.0%) patients with low PSMA expression and PSMA-negative lesions, respectively. The VISION-PET-SF patients had worse PSA50RR (21% vs 50%; p = 0.005), anyPSARR (41% vs 71%; p = 0.003), median PSA PFS (2.1 months (95%CI: 1.1-3.3) vs. 4.1 (4.0-5.8); p = 0.023)), and tended to have a shorter OS (9.6 months (95%CI: 4.7-14.0) vs. 14.2 (12.6-15.9); p = 0.16) than the VISION-PET-E patients. Conclusions: VISION-PET-SF patients had worse outcomes than the VISION-PET-E patients. Our cohort only included patients who were eligible by each local site criteria. It did not include those 10-15% of patients who were excluded by local site assessment. Thus, 20-25% of the patients may be screen failures in unselected populations. Refinements in patient selection for 177Lu-PSMA are needed to optimize outcomes. Not characterizing target expression prior to PSMA-targeted treatment appears now non-ethical as a predictive whole-body imaging biomarker for response to PSMA-targeted therapies is available.
The cost of living: an avoidable public health crisis
Authors: None The Lancet Public Health
Journal: The Lancet Public Health (2022)

A global recession looms. Disruptions to supply chains—caused by the COVID-19 pandemic, the climate crisis, and the Russian invasion of Ukraine—have pushed the cost of living up dramatically for millions of people around the world. Governments have cut back on the social protections communities had come to rely on during the pandemic. As annual inflation rates in high-income countries approach 10%, a growing number of people are being forced to choose between feeding their children and paying their bills.
Neoadjuvant survivin-targeted immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor-positive (HR+) early-stage breast cancer (ESBC).
Authors: Sasha E. Stanton, Lisa Diana MacDonald, Staci L. Mellinger, Nicole Moxon, Tracy Kelly, Heather Anne Hirsch, Stephan Fiset, Kristina Hoot Young, David B. Page
Journal: Journal of Clinical Oncology (2022)

TPS1119 Background: HR+ ESBC is associated with suboptimal pathologic complete response rate (pCR, ̃10%) following neoadjuvant cytotoxic chemotherapy. Neoadjuvant anti-endocrine therapy with aromatase inhibitors (AI) may serve as an effective alternative. Efficacy can be gauged using the surrogate Ki67 cell proliferation histologic marker. Patients with poor Ki67 response (defined as Ki67 &gt; 10%) following neoadjuvant AI exhibit poor prognosis and therapeutic resistance to both anti-endocrine therapy and chemotherapy. In a genomic analysis among Ki67-high HR+ tumors, we identified 8-fold upregulation of BIRC5 (survivin), a gene that regulates apoptosis and the cell cycle and that is associated with poor clinical outcome. Maveropepimut-S (MVP-S, previously named DPX-Survivac) leverages the non-aqueous, lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from Survivin, a cancer-associated protein commonly upregulated in several cancers. Treatment with MVP-S and intermittent, low-dose cyclophosphamide (CPA) has shown tumor infiltration of survivin-specific T cells. Previous clinical trials have shown that MVP-S is well-tolerated, immunogenic, and could lead to clinical response in several cancer indications. Further exploration of the regimen in breast cancer could extend the application of this immunotherapy for this unmet medical need. Methods: NCT04895761 is phase I trial evaluating the safety and immunologic effects of neoadjuvant MVP-S plus letrozole (arm A, n = 6), with/without tumor-directed MR-guided radiotherapy (arm B, n = 6), or intermittent low-dose cyclophosphamide or CPA (arm C, n = 6). Postmenopausal patients with T1c+ HR+HER2- breast cancer with Ki67 &gt; 10% will receive two doses of MVP-S and 7 weeks of neoadjuvant letrozole prior to surgery (all arms), whereas arm B will be treated additionally with concurrent 10Gy x 2 tumor boost radiation to facilitate immunogenic cell death, and arm C (n = 6) will be treated additionally with intermittent low-dose CPA (50mg BID) to facilitate regulatory T cell depletion. The primary objective is safety. Biomarker objectives are to evaluate for each treatment arm: 1) systemic type I survivin-specific immune response, as measured by IFN-γ ELISPOT; 2) changes in immune environment by GeoMx digital spatial genomic profiling; 3) and changes in tumor infiltrating lymphocytes (TILs) and Ki67. These data will be used to identify the most immunogenic MVP-S combination therapy for study in phase II trial powered to assess clinical outcome (pCR). Clinical trial information: NCT04895761.
Second primary malignancy in stage I and II breast cancer survivor: A United States population-based study.
Authors: Mohammed Abdulhaleem
Journal: Journal of Clinical Oncology (2022)

e12579 Background: In United States, breast cancer accounts for over 260,000 cases each year and is responsible for over 40,000 deaths. Survival primarily depends on the stage at time of diagnosis. 5-year survival among early breast cancer is more than 50%. It is known that patients with cancer undergoing treatment have a significant risk of developing a second primary malignancy (SPM); we aimed to focus our study at the incidence of various SPM among patients surviving stage I and II breast cancer, which can help in their targeted surveillance. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute to select adult patients (18 and above) diagnosed with stage I and II breast cancer as their first malignancy between January 2000 and December 2015. This is one of the largest cancer registries worldwide. SPM is metachronous cancer which develops six months after an index localized breast cancer diagnosis based on Warren and Gates criteria. Multiple primary standardized incidence ratios (MP-SIR) and absolute excess risk (AER) for an occurrence of SPM were obtained utilizing SEER. SIR is observed to expected incidence ratio (O/E) of SPM and AER, it is an actual number of excess SPMs in patients with early breast cancer per 10,000 person-years at risk. Statistical significance was defined as a p-value ≤ 0.05. Results: We localized 513,408 patients with a diagnosis of stage I and II breast cancer from 2000 - 2015. Patients were followed for a median duration of 8.92 years (range 0.5 to 15.92). Of these patients, 81.5% were white. About 8.6% (43938) of patients developed 47708 primary malignancies. These malignancies were significantly higher than the general population with O/E ratio of 1.15 and AER of 17.12. The median age of diagnosis of SPM was 69.8 years (range 22.8 – 105.08 years). The average latency to develop SPM was 5.28 years (range 0.5 – 15.92 years). Among solid tumors, a statistically significant increased risk was observed with salivary gland, tongue, gastric, colon, lung cancer, and genitourinary cancers. Among hematological malignancies, statistically significant risk was seen for ALL, AML and CML. The risk of hepatobiliary, CNS cancers and lymphoma were significantly lower among our cohort included in current study. The SPM was found significantly increased after the latency of 24 months, and the risk of SPM was greater across all age groups. Conclusions: Due to robust breast cancer screening strategies, a significantly higher proportion of the patients are diagnosed early in the course of the disease which tends to be curative and this group of patients has better survival rates. Our study recognizes that the risk of certain SPM is higher in stage I and II breast cancer survivals compared to general population; and they would benefit from guidelines that can identify cancer with increased risk in these patients population.
Effect of Deintensifying Diabetes Medications on Negative Events in Older Veteran Nursing Home Residents
Authors: Joshua D. Niznik, Xinhua Zhao, Florentina Slieanu, Maria K. Mor, Sherrie L. Aspinall, Walid F. Gellad, Mary Ersek, Ryan P. Hickson, Sydney P. Springer, Loren J. Schleiden, Joseph T. Hanlon, Joshua M. Thorpe, Carolyn T. Thorpe
Journal: Diabetes Care (2022)

OBJECTIVE Guidelines advocate against tight glycemic control in older nursing home (NH) residents with advanced dementia (AD) or limited life expectancy (LLE). We evaluated the effect of deintensifying diabetes medications with regard to all-cause emergency department (ED) visits, hospitalizations, and death in NH residents with LLE/AD and tight glycemic control. RESEARCH DESIGN AND METHODS We conducted a national retrospective cohort study of 2,082 newly admitted nonhospice veteran NH residents with LLE/AD potentially overtreated for diabetes (HbA1c ≤7.5% and one or more diabetes medications) in fiscal years 2009–2015. Diabetes treatment deintensification (dose decrease or discontinuation of a noninsulin agent or stopping insulin sustained ≥7 days) was identified within 30 days after HbA1c measurement. To adjust for confounding, we used entropy weights to balance covariates between NH residents who deintensified versus continued medications. We used the Aalen-Johansen estimator to calculate the 60-day cumulative incidence and risk ratios (RRs) for ED or hospital visits and deaths. RESULTS Diabetes medications were deintensified for 27% of residents. In the subsequent 60 days, 28.5% of all residents were transferred to the ED or acute hospital setting for any cause and 3.9% died. After entropy weighting, deintensifying was not associated with 60-day all-cause ED visits or hospitalizations (RR 0.99 [95% CI 0.84, 1.18]) or 60-day mortality (1.52 [0.89, 2.81]). CONCLUSIONS Among NH residents with LLE/AD who may be inappropriately overtreated with tight glycemic control, deintensification of diabetes medications was not associated with increased risk of 60-day all-cause ED visits, hospitalization, or death.
Prognostic significance of raised serum tumor markers (STM) after 2 cycles of chemotherapy in men with intermediate- and poor-risk non-seminomatous testicular germ cell tumors (NSGCT) treated at a single-centre in India.
Authors: ANKUR NANDAN VARSHNEY, Abhishek Raj, Ranjit Kumar Sahoo, Haresh KP, Prabhjot Singh, Shamim Ahmed Shamim, Amlesh Seth, M D INDIA INSTITUTE OF MEDICAL Ray, Seema Kaushal, Chandan Krushna Das, Atul Batra
Journal: Journal of Clinical Oncology (2022)

5036 Background: Testicular GCT is a rare malignancy, with excellent outcomes. However, approximately one-fourth of intermediate risk and half of the patients with poor risk disease succumb to recurrent GCT. We looked at the prognostic significance of raised serum tumor markers after 2 cycles of chemotherapy in patients with poor risk GCT. Methods: This is a chart-review based retrospective analysis of patients with intermediate and poor risk NSGCT diagnosed and treated at a tertiary care centre in New Delhi, India from 2015-2021. Risk categories were defined as per the International Germ Cell Cancer Collaborative Group. Multivariable Cox regression models were constructed to analyse the prognostic impact of normal STM at the end of second cycle of chemotherapy on overall survival (OS) and relapse free survival (RFS), while adjusted for measured confounders. Results: A total of 312 patients were identified with testicular NSGCT, of whom 109 were intermediate (n = 48, 44%) and poor risk (n = 61, 56%). The median age at diagnosis was 27 (interquartile range, 21-34) years. ECOG PS of patients was 0-1 in 51% and 2-4 in 49%, and poor risk patients were more likely to have a poor ECOG PS at diagnosis (70% vs 30%, P &lt; 0.001). First-line chemotherapy was BEP in 86% patients and VIP in the remaining 14%, and surgery for residual disease was performed in 22%. Overall, 35% patients had normal STM after 2 cycles of chemotherapy, and patients with intermediate risk were likely to achieve normal STM at this time-point (50% vs 23%). At a median follow-up of 62 months, the 5-year RFS rate was 62% (poor risk 52% and intermediate risk 78%), and OS rate was 68% (58% and 80%, respectively). Men with normal STM after 2 cycles chemotherapy had a better RFS (hazard ratio [HR], 0.70; 95% confidence interval 0.48-0.81; P &lt; 0.001) and OS (HR,0.82; 95% CI 0.61-0.99; P = 0.04). After adjusting for risk category, and ECOG PS in a multivariable Cox regression model, patients with normal STM at the end of 2 cycles of chemo continued to have better outcomes (adjusted HR for RFS, 0.78; 95% CI, 0.77-0.89; P = 0.03, and adjusted HR for OS, 0.92; 95% CI,0.81-0.99; P = 0.05). Intermediate risk NSGCT and good ECOG PS also predicted better RFS and OS. Conclusions: Patients with NSGCT whose STMs do not normalize after 2 cycles of chemotherapy have worse RFS and OS compared to those with normal STM at this time-point. Further clinical trials will be needed to study the role of escalation or switch of chemotherapy in this subset of population.
Organoids in gastrointestinal diseases: from experimental models to clinical translation
Authors: Claudia Günther, Beate Winner, Markus F Neurath, Thaddeus S Stappenbeck
Journal: Gut (2022)

We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
Molecular correlates of <i>MAEA</i> expression in colorectal cancer (CRC).
Authors: Shivani Soni, Francesca Battaglin, Yasmine Baca, Joanne Xiu, Pavel Brodskiy, Jae Ho Lo, Sandra Algaze, Priya Jayachandran, Hiroyuki Arai, Wu Zhang, Benjamin Adam Weinberg, Emil Lou, Pat Gulhati, Mohd Khushman, Anthony Frank Shields, Richard M. Goldberg, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2022)

3128 Background: Macrophage Erythroblast Attacher (MAEA) plays an important role in actin cytoskeleton rearrangement in macrophages and erythroid cells. We previously reported that MAEA suppresses migration, invasion and enhances chemosensitivity in CRC cell lines. Here we aimed to characterize the molecular features associated with MAEA gene expression in CRC. Methods: 14416 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for MAEA expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X 2 and Fisher-Exact tests were used and significance was determined as P-value adjusted for multiple comparisons ( Q &lt; 0.05). Results: MAEA expression was highest in rectal tumors (13.6 median TPM) followed by transverse and right-sided tumors (13.0 and 12.8, respectively) and lowest in left-sided tumors (12.5). Overall, MAEA TPM were associated with higher tumor mutational burden (≥ 10 Mut/Mb) (11.8% vs. 8.2%) and dMMR/MSI-H (8.7% vs. 5.1%) ( Q &lt; 0.0001); however, the association with TMB was not observed in MSS tumors. In the MSS cohort, MAEA expression was the highest in CMS4 (14.9 median TPM) followed by CMS1 (12.5), CMS2 (11.9), and the lowest in CMS3 (10.3, all intergroup Q &lt; 0.05). MAEA high was associated with lower mutation rates of APC and amplification of FLT1/ FLT3 while higher mutation rates of ASXL1, KMT2A/C/D, SMARCA4, FBXW7, PTEN, RNF43, BRCA2, HNF1A in the overall cohort ( Q &lt; 0.05). In the MSS cohort, FBXW7 mutation significance with MAEA high expression held true ( Q &lt; 0.05) while MAEA high expression trended to associate with higher mutation rates of KMT2D, SMARCA4, PTEN, BRCA2 mutations, and a lower frequency of FLT1/ FLT3 CNA ( P &lt; 0.05 but Q &gt; 0.05). High MAEA was associated with higher immune CI in the TME, including B cells, macrophages (M1 and M2), neutrophils, NK cells, Tregs, CD4+ T cells and myeloid dendritic cells both in the overall cohort and in MSS tumors (fold change: 1.11-1.33, all Q &lt; 0.001). Conclusions: Our data show a strong association between MAEA gene expression and distinct molecular features (including CMS and immune biomarkers) and TME cell infiltration in CRC. These findings suggest that targeting MAEA may have relevant clinical applications in selected CRC subgroups and MAEA may be an important player in determining the composition of the TME.